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Synthetic ligands of death receptor 5 display a cell-selective agonistic effect at different oligomerization levels
DR4 (Death Receptor 4) and DR5 (Death Receptor 5) are two potential targets for cancer therapy due to their ability to trigger apoptosis of cancer cells, but not normal ones, when activated by their cognate ligand TRAIL (TNF related apoptosis-inducing ligand). Therapies based on soluble recombinant...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5323128/ https://www.ncbi.nlm.nih.gov/pubmed/27409341 http://dx.doi.org/10.18632/oncotarget.10508 |
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author | Beyrath, Julien Chekkat, Neila Smulski, Cristian R. Lombardo, Caterina M. Lechner, Marie-Charlotte Seguin, Cendrine Decossas, Marion Spanedda, Maria Vittoria Frisch, Benoît Guichard, Gilles Fournel, Sylvie |
author_facet | Beyrath, Julien Chekkat, Neila Smulski, Cristian R. Lombardo, Caterina M. Lechner, Marie-Charlotte Seguin, Cendrine Decossas, Marion Spanedda, Maria Vittoria Frisch, Benoît Guichard, Gilles Fournel, Sylvie |
author_sort | Beyrath, Julien |
collection | PubMed |
description | DR4 (Death Receptor 4) and DR5 (Death Receptor 5) are two potential targets for cancer therapy due to their ability to trigger apoptosis of cancer cells, but not normal ones, when activated by their cognate ligand TRAIL (TNF related apoptosis-inducing ligand). Therapies based on soluble recombinant TRAIL or agonist antibodies directed against one of the receptors are currently under clinical trials. However, TRAIL-R positive tumor cells are frequently resistant to TRAIL induced apoptosis. The precise mechanisms of this resistance are still not entirely understood. We have previously reported on synthetic peptides that bind to DR5 (TRAIL(mim/DR5)) and induce tumor cell apoptosis in vitro and in vivo. Here, we showed that while hexameric soluble TRAIL is able to efficiently kill the DR5 positive lymphoma Jurkat or the carcinoma HCT116, these cells are resistant to apoptosis induced by the divalent form of TRAIL(mim/DR5) and are poorly sensitive to apoptosis induced by an anti-DR5 agonist monoclonal antibody. This resistance can be restored by the cross-linking of anti-DR5 agonist antibody but not by the cross-linking of the divalent form of TRAIL(mim/DR5). Interestingly, the divalent form of TRAIL(mim/DR5) that induced apoptosis of DR5 positive BJAB cells, acts as an inhibitor of TRAIL-induced apoptosis on Jurkat and HCT116 cells. The rapid internalization of DR5 observed when treated with divalent form of TRAIL(mim/DR5) could explain the antagonist activity of the ligand on Jurkat and HCT116 cells but also highlights the independence of the mechanisms responsible for internalization and activation when triggering the DR5 apoptotic cascade. |
format | Online Article Text |
id | pubmed-5323128 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-53231282017-03-23 Synthetic ligands of death receptor 5 display a cell-selective agonistic effect at different oligomerization levels Beyrath, Julien Chekkat, Neila Smulski, Cristian R. Lombardo, Caterina M. Lechner, Marie-Charlotte Seguin, Cendrine Decossas, Marion Spanedda, Maria Vittoria Frisch, Benoît Guichard, Gilles Fournel, Sylvie Oncotarget Research Paper DR4 (Death Receptor 4) and DR5 (Death Receptor 5) are two potential targets for cancer therapy due to their ability to trigger apoptosis of cancer cells, but not normal ones, when activated by their cognate ligand TRAIL (TNF related apoptosis-inducing ligand). Therapies based on soluble recombinant TRAIL or agonist antibodies directed against one of the receptors are currently under clinical trials. However, TRAIL-R positive tumor cells are frequently resistant to TRAIL induced apoptosis. The precise mechanisms of this resistance are still not entirely understood. We have previously reported on synthetic peptides that bind to DR5 (TRAIL(mim/DR5)) and induce tumor cell apoptosis in vitro and in vivo. Here, we showed that while hexameric soluble TRAIL is able to efficiently kill the DR5 positive lymphoma Jurkat or the carcinoma HCT116, these cells are resistant to apoptosis induced by the divalent form of TRAIL(mim/DR5) and are poorly sensitive to apoptosis induced by an anti-DR5 agonist monoclonal antibody. This resistance can be restored by the cross-linking of anti-DR5 agonist antibody but not by the cross-linking of the divalent form of TRAIL(mim/DR5). Interestingly, the divalent form of TRAIL(mim/DR5) that induced apoptosis of DR5 positive BJAB cells, acts as an inhibitor of TRAIL-induced apoptosis on Jurkat and HCT116 cells. The rapid internalization of DR5 observed when treated with divalent form of TRAIL(mim/DR5) could explain the antagonist activity of the ligand on Jurkat and HCT116 cells but also highlights the independence of the mechanisms responsible for internalization and activation when triggering the DR5 apoptotic cascade. Impact Journals LLC 2016-07-09 /pmc/articles/PMC5323128/ /pubmed/27409341 http://dx.doi.org/10.18632/oncotarget.10508 Text en Copyright: © 2016 Beyrath et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Beyrath, Julien Chekkat, Neila Smulski, Cristian R. Lombardo, Caterina M. Lechner, Marie-Charlotte Seguin, Cendrine Decossas, Marion Spanedda, Maria Vittoria Frisch, Benoît Guichard, Gilles Fournel, Sylvie Synthetic ligands of death receptor 5 display a cell-selective agonistic effect at different oligomerization levels |
title | Synthetic ligands of death receptor 5 display a cell-selective agonistic effect at different oligomerization levels |
title_full | Synthetic ligands of death receptor 5 display a cell-selective agonistic effect at different oligomerization levels |
title_fullStr | Synthetic ligands of death receptor 5 display a cell-selective agonistic effect at different oligomerization levels |
title_full_unstemmed | Synthetic ligands of death receptor 5 display a cell-selective agonistic effect at different oligomerization levels |
title_short | Synthetic ligands of death receptor 5 display a cell-selective agonistic effect at different oligomerization levels |
title_sort | synthetic ligands of death receptor 5 display a cell-selective agonistic effect at different oligomerization levels |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5323128/ https://www.ncbi.nlm.nih.gov/pubmed/27409341 http://dx.doi.org/10.18632/oncotarget.10508 |
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